Novel Treatment of menopausal hot flushes with an extradiol prodrug

描述（由申请人提供）：潮热在全球范围内构成重大的公共卫生问题。这些围绝经期症状是妇女在绝经过渡期寻求医疗护理的主要原因。潮热通常会对女性的生活质量产生负面影响，因为它们与睡眠障碍有关，导致疲劳，抑郁，易怒和健忘，以及急性身体不适和对工作的负面影响。目前的疗法包括雌激素或激素（雌激素+孕激素）疗法（ERT和HRT）、可乐定、选择性5-羟色胺和/或去甲肾上腺素再摄取抑制剂和加巴喷丁。尽管ERT或HRT在预防潮热方面有效，但大量女性不能或不想服用雌激素。其他疗法的疗效值得怀疑。因此，对于更好和更安全的ERT或HRT存在巨大的未满足的需求。在本申请中，我们提出17 b-雌二醇的对苯二酚（Q-E1）有可能被认为是最佳的ERT。我们先前已经表明雌酮的对苯二酚（Q-E1）作为前药发挥作用，并且在其吸收后，其在选择性组织中通过涉及NADP（H）的酶催化机制转化为E1。这种转换在大脑中有效，但在子宫、乳房或脑垂体中无效。因此，雌激素的醌醇类治疗不像任何其他雌激素（包括常用的倍美力）那样具有促子宫（斑点，出血，癌症）和促乳房（乳腺癌）的倾向。由于E2是人类卵巢产生的主要和最有效的雌激素，我们建议考虑Q-E2作为治疗围绝经期症状的前药，主要是潮热。我们的初步数据强烈表明，Q-E2在大鼠潮热模型中阻断潮热症状，但在阻断潮热症状的剂量下不会刺激MCF-7乳腺细胞或子宫的增殖。因此，Q-E2似乎是一种新型、安全和最佳的缓解围绝经期潮热的ERT。该提案描述了一系列研究，旨在（i）解剖出参与体温调节的脑区中Q-E2/E2转换的动力学，（ii）使用两种大鼠潮热模型建立皮下和口服给药后Q-E2的最佳剂量，（iii）提供证据证明Q-E2的有益作用是通过雌激素受体介导的，和（iv）证实对切除卵巢的大鼠长期给药后，在子宫和乳房中没有作用，而在骨中有有益作用。新型安全ERT的发现将改善全球数亿围绝经期妇女的生活质量，从而对公共卫生产生巨大影响。虽然还没有经过实验测试，Q-E2也可能是男性更年期的治疗选择。此外，我们在这里提出的前药方法可以为其他相关或非相关疗法的药物发现提供动力。公共卫生相关性：围绝经期潮热在全球范围内引起了严重的公共卫生问题。虽然激素替代疗法可以缓解大多数妇女的潮热，但大量围绝经期妇女不能服用或不想服用激素。因此，对于更年期症状的更好和更安全的疗法仍然存在巨大的未满足的需求。该提案通过研究一种潜在的无责任雌激素替代疗法来解决这一未满足的需求，即，使用对苯二酚作为雌激素前药的方法。前药在大脑中转化为雌激素，但在子宫和乳房中不转化为雌激素，因此，它在潮热动物模型中减弱潮热。

DESCRIPTION (provided by applicant): Hot flushes pose a significant public health concern world-wide. These perimenopausal symptoms are the primary reason that women seek medical care during the menopausal transition. Hot flushes often negatively impact the quality of life of women because they are associated with sleep disturbances resulting in fatigue, depression, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work. Current therapies include estrogen or hormone (estrogens + progestins) therapies (ERT and HRT), clonidine, the selective serotonin and/or norepinephrine reuptake inhibitors, and gabapentine. Although ERT or HRT is efficacious in preventing hot flushes, a large number of women cannot or do not want to take estrogen. The efficacy of the other therapies is questionable. Therefore, there is a huge unmet need for a better and safer ERT or HRT. We propose in this application that para-quinol of 17b-estradiol (Q-E1) has the potential to be considered as the optimal ERT. We have shown earlier that para-quinol of estrone (Q-E1) functions as a pro-drug and following its absorption its is converted in selective tissues to E1 via an enzyme catalyzed mechanism involving NADP(H). This conversion is effective in the brain but not in the uterus, breast, or the pituitary gland. Therefore, treatment with quinols of estrogens do not have uterotropic (spotting, bleeding, cancer) and mammotropic (breast cancer) liabilities like any other estrogens, including the frequently used Premarin. Since E2 is the primary and most potent estrogen produced by the human ovary, we propose to consider Q-E2 as a pro-drug for the treatment of perimenopausal symptoms, primarily hot flushes. Our pilot data strongly indicate that Q-E2 blocks hot flush symptoms in a rat model of hot flush, but does not stimulate proliferation in MCF-7 breast cells or the uterus at doses that block the hot flush symptoms. Therefore, Q-E2 seems to be a novel, safe, and optimal ERT for alleviating perimenopausal hot flushes. The proposal describes a series of studies aimed at (i) dissecting out the dynamics of Q-E2/E2 conversion in brain areas involved in thermoregulation, (ii) establishing the optimal dose of Q-E2 following its subcutaneous and oral administration using two rat models of hot flush, (iii) provide evidence that the beneficial actions of Q-E2 are mediated via estrogen receptors, and (iv) confirm the lack of action in the uterus and breast, and the beneficial effects in the bone following its chronic administration to ovariectomized rats. The discovery of a novel and safe ERT would improve the quality of life of hundreds of millions of perimenopausal women world-wide and thus, would have a tremendous impact on public health. Although has not been tested experimentally, Q-E2 might be the choice of therapy of men in the andropause as well. In addition, the pro-drug approach we propose here could provide an impetus for drug discovery of other related or un-related therapies. PUBLIC HEALTH RELEVANCE: Peri-menopausal hot flushes pose a significant public health concern world-wide. Although hormone replacement therapy, alleviates hot flushes in the majority of women, a large number of peri-menopausal women cannot take or do not want to take hormones. Therefore, there is still a huge unmet need for better and safer therapies for menopausal symptoms. The proposal addresses this unmet need by investigating a potentially liability-free estrogen replacement therapy, i.e., the use of para-quinol of estrogen as a prodrug approach. The prodrug is converted to estrogen in brain but not uterus and breast, and as a result, it blunts hot flushes in an animal model of hot flush.